Manipulating interferon levels toward a safe and effective live single-cycle pediatric RSV vaccine

About This Grant

SUMMARY RSV is the largest viral cause of pediatric bronchiolitis and pneumonia, causing >100,000 deaths in children worldwide. Recently, the FDA approved a maternal vaccine to protect newborns. This vaccine is given to pregnant women to protect infants in the first months of life via passively acquired antibodies. This modality is a momentous step forward in the battle against RSV. However, as maternal antibodies wane, infants > 4-6 months remain vulnerable. In addition, not all may elect a vaccine in the third trimester; For this and other reasons, the young infant population will likely continue to present a range of protective Ab levels. Moreover, the burden of RSV disease and cost is high for children up to 4-5 years of age, and a vaccine to directly induce immunity in infants and children remains a priority. Intranasally applied live vaccines are an attractive approach as they induce a response that is broad (humoral, cellular, multi-antigenic i.e. not dependent on a single antigen) and includes mucosal immunity, which provides protection against upper respiratory tract infection and virus spread in the population. The primary aim of this proposal is to generate and test a novel live-attenuated vaccine for neonatal infants (< 28 days). However, live vaccines, especially in neonates, have unique safety/efficacy challenges. To prevent live vaccine reversion to virulence, we previously developed intranasal single-cycle RSV vaccines (see 'Significance'). Single-cycle vaccines are live and produce high levels of viral antigens, but are blocked in cell-cell transmission and cannot revert to virulence, including in context of suboptimal immunity. In adult mice, prime-boost vaccination with single-cycle vaccine induced broad, robust, immunity and protected mice from challenge. Another challenge for live neonatal vaccines is immunologic immaturity. Whereas this may explain generally weak neonatal responses, some studies suggest that even young infants have potential to induce high Ab titers. Immaturity can however lead to unbalanced Thelper cell responses (Th2-bias) and related immunopathology after re-exposure to RSV, reminiscent of a failed trial in the 1960s using inactivated RSV vaccine. A main factor believed to underlie neonatal Th2 bias is a weak early type I interferon (IFN) response, as addition of exogenous IFN alleviated the bias. For an effective vaccine, we propose to improve the IFN response through distinct mechanisms (blocking viral IFN antagonism, and integration of IFN expressing genes) and to test the impact in a neonatal mouse model. In addition, our vaccine design focuses the fusion and attachment protein responses for improved cross-efficacy, and it's intranasal route of vaccination should reduce inhibition by maternal antibodies, which we will investigate. We expect the combined enhancements to deliver a prime-boost vaccine that is both safe (no Th2 bias) and efficacious (protective against multiple strains) with a prime vaccination given at a neonatal age. Finally, we also investigate neonatal versus post-neonatal prime-vaccination. This broadens the impact of our study to include potential for alternatives, such as a post-neonatal vaccination modality (prime at 1-4 months) or a modality to work in conjunction with the Pfizer maternal vaccine (prime at 4-6 months).